Schaumburg, IL,Sagent Pharmaceuticals, Inc. announced on February 23, 2015 the voluntary nationwide recall of two lots of Atracurium Besylate Injection, USP, 50mg/5mL single-dose vials (NDC 25021-659-05) and four lots of Atracurium Besylate Injection, USP, 100mg/10mL multi-dose vials (NDC 25021-672-10) manufactured by Emcure Pharmaceuticals Ltd. and distributed by Sagent. Sagent has initiated this voluntary recall of Atracurium Besylate Injection, USP, 50mg/5mL and 100mg/10mL to the user level due to FDA observations pertaining to aseptic and GMP practices at the manufacturer’s site potentially impacting product sterility. Non-sterility of a drug administered via the intravenous route has the potential to result in infections, which could be fatal, especially in patients who are immunocompromised. Sagent has transferred the manufacture of this product to its own facility and this product manufactured at the Sagent facility will not be impacted by the recall.

Sagent is not aware of any adverse patient events resulting from the use of the subject product lots.

The lot numbers being recalled are VATA012, VATA015 (50mg/5mL) and VATB012, VATB013, VATB014, VATB017 (100mg/10mL) which were distributed to hospitals, wholesalers and distributors nationwide from February 2014 through February 2015. Atracurium Besylate Injection, USP, 50mg/5mL and 100mg/10mL is indicated, as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation, and is supplied in single-dose and multi-dose vials.

During a June 23, 2014 through July 1, 2014, inspection of the Apotex Research Private Limited (ARPL) manufacturing facilities located at Plot #1 & 2, Bommasandra Ind. Area, 4th Phase, Jigani Link Road, Bangalore, India, investigators from the U.S. Food and Drug Administration (FDA) identified significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These violations caused their drug products to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 351(a)(2)(B), in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding did not conform to, or are not operated or administered in conformity with, CGMP.

The FDA conducted a detailed review of the firm’s response dated July 22, 2014 and noted that it lacks sufficient corrective actions. They also acknowledged receipt of the firm’s additional correspondence dated August 11, 2014, August 29, 2014, September 30, 2014, October 31, 2014, December 5, 2014 and January 9, 2015.

The investigators observed specific violations during the inspection, including, but not limited to, the following:

Your firm failed to establish and follow appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile (21 CFR 211.113(a)).

Finished drug product (b)(4) Tablets (b)(4)mg batches (b)(4) and (b)(4) microbial sample plates/tubes were placed in the incubators on June 19-20, 2014, as documented in your LIMS computer system. The plates should have been incubated for (b)(4) days, per your procedures. On June 23, 2014, no plates/tubes for this batch were observed in any of the incubation chambers.

Finished drug product (b)(4) Tablets (b)(4) mg Exhibit Batch (b)(4) sample for microbial testing was prepared on June 13, 2014. Your firm failed to provide the FDA investigator with the worksheet to document the incubation times and media used for the analysis. Your analyst described that the entire microbial test for this batch had already been completed the previous week but that the analyst had “forgotten” to document the details on the worksheet.

The FDA investigator noted other instances of missing samples/plates for in-process drug products, potable water, and growth promotion, even though records indicated that they were in the incubator.

As a result of the above observation, your firm initiated an investigation and reported that 290 (b)(4) plates and 36 media tubes under testing were missing, affecting 45 product sample batches, 12 growth promotion test batches, and 37 negative control plates. Your firm also found discrepancies between the documentation and location of samples/plates and you indicated that the majority of the missing plates were found in the decontamination area for disposal.

In your response, you refer to an investigation and indicate that “…two analysts momentarily panicked (upon (1) learning that FDA Investigators were approaching the microbiology Lab and (2) seeing used petri plates from the weekend scattered throughout the laboratory)[sic] and directed the lab technician to immediately remove the petri plates from the microbiology lab … in an utterly misguided and ill-conceived attempt to clean up the microbiology lab prior to the start of the FDA inspection.”

Your response lacks a comprehensive risk assessment of your failure to follow procedures, your inadequate documentation system and your inadequate practices related to microbiological control. Your response failed to evaluate the effect of these violations on product quality, and did not include an assessment as to whether any other batches have been compromised.

ARPL’s inability to prevent and detect poor recordkeeping practices raises serious concerns regarding the quality system in place at the time of the inspection. Appropriate controls are essential to assure that the information used for making decisions is trustworthy, accurate, and reliable.”

COMMENT:

When a firm fails with its procedures and recordkeeping practices, the Agency will consider these issues part of a larger problem to include Quality System issues. It is somewhat difficult to believe that the technician and the analysts panicked to such a degree that plates would be removed from the laboratory because the FDA Investigators were arriving. One would think that the entire facility would be aware of the FDA’s presence and continually maintain the facilities in a pristine condition. The failure to follow procedures, have good documentation practices and maintain microbiological control suggests a lack of training and proper internal management skills.

In addition, the dates of the incubation vs. the arrival of the FDA did not “hold water”. The FDA could readily review the dates of incubation to determine when plates and tubes would complete their incubation period based upon the Company’s SOPs and USP<61>. These forms of fabrication only cause the FDA to review the laboratory’s data in additional detail.

FOR IMMEDIATE RELEASE — Oct. 25, 2014 — MCELHATTAN, PA — Nutek Disposables, Inc. of McElhattan, PA has initiated a nationwide voluntary product recall at the retail level of all lots of baby wipes that it manufactured under the brand names Cuties, Diapers.com, Femtex, Fred’s, Kidgets, Member’s Mark, Simply Right, Sunny Smiles, Tender Touch, and Well Beginnings, because some packages may contain bacteria. These wipes were distributed by Nutek prior to October 21, 2014 to the following retail stores: Walgreens, Sam’s Club, Family Dollar, Fred’s, and Diapers.com.

After receiving a small number of complaints of odor and discoloration, Nutek conducted microbial testing that showed the presence of a bacteria, called Burkholderia cepacia (B. cepacia), in some of these products. Soon after, on October 3, 2014 the company initiated a voluntary withdrawal of lots that had tested positive for the bacteria, as well as other baby wipes in the surrounding time frame. After some additional lots were tested, as a precautionary measure, Nutek believed it was a prudent decision to withdraw all its baby wipe products.

B. cepacia poses little medical risk to healthy people. However, people who have certain health problems like weakened immune systems or chronic lung diseases, particularly cystic fibrosis, may be more susceptible to infections with B. cepacia. If you believe you have a weakened immune system or chronic lung disease and you have used one of the affected wipe products, you should call your doctor promptly for medical advice.

As of October 3, 2014, the date of the original withdrawal, the company had received only one report of irritation. Numerous reports of complaints have since been received by the company that include rash, irritation, infections, fever, gastro-intestinal issues, and respiratory issues, though these reports have not been confirmed to be related to the use of these products.

The company has not identified the cause of the problem, but is continuing to investigate. In the interim, Nutek has stopped shipping baby wipes manufactured at the facility.

Nutek takes the safety of consumers and the quality of its products very seriously and is taking all appropriate steps to address the issue and ensure this does not happen again.

The company is working with the U.S. Food & Drug Administration and the affected retailers and distributors throughout this process to address the issue.

COMMENT:

An article called “Burkholderia cepacia: The Decision is Overdue” was written by Torbeck etal in October 2011. Within this article they discuss B. cepacia and the various microbiological problems that may be encountered within medical devices and drugs. They note that water sources remain an excellent source of the bacterium which may survive in water for weeks, but only days on solid surfaces.

Within the Recall the Company (Nutek) had not identified the cause of the problem, but was continuing to investigate. I would encourage Nutek to review this article from 2011 and consider the following potential causes that they list.

They include:

Inadequate cleaning procedures

Use of unsuitable grade of water (g., use of potable water to clean the process equipment)

Poor water system control (g., lack of proper sanitization, failure to validate and lack of scheduled maintenance)

Poor water systems design (g., stagnant water allowed biofilm development

The authors proceed to indicate that water was implicated within six recalls, while contaminated raw materials were implicated three recalls and inadequate testing before distribution was implicated in two recalls.

White & Blue Lion, Inc, City of Industry, CA recently recalled all lots of tattoo inks and tattoo needles due to pathogenic bacterial contamination. The recall indicated that the “use of these products may cause bacterial infection and can lead to sepsis, a potentially life-threatening complication of an infection. The recall includes all tattoo ink, tattoo needles, tubes, ink cups and kits…”

FDA laboratory testing has found bacterial contamination in both the inks and needles.

A variety of potentially pathogenic microorganisms were isolated from the tattoo kits (ink and needles) to include: Gram negative bacteria, Gram positive rods and cocci, which were identified as Bacillus spp., Sphingomonas paucimobilis, Micrococcus lutes, Corynebacterium spp., Clostridium botulinum and other Clostridium spp. The recall made a point that no mycobacteria were isolated.

A variety of potentially pathogenic organisms were also isolated and identified from the ink sets. These included Gram negative bacteria, Gram positive rods and cocci which were further identified as Bacillus spp., Acinetobacter spp., Staphylococcus haemolyticus, and Sphingomonas paucimobilis.

This recall was made with the knowledge of the US Food and Drug Administration.

ISSUES INCLUDE MOLD GROWTH AT STERILE MANUFACTURING ENTRY AND DEAD AND DECAYING FROGS NEAR THE PRODUCT EXIT DOCK

Between October 29 and November 1, 2013, the FDA inspected Marck Biosciences Ltd., Kheda, India. As a consequence of this audit, the FDA issued six extensive Observations. This Blog only reviews Observation 5 (a) and 5 (b).

“Your firm failed to maintain the buildings used in the manufacture, processing, packing, or holding of a drug product in a clean and sanitary condition and keep them free of infestation by rodents, birds, insects, and other vermin (21 CFR 211.56(a)).

COMMENT

Other sections of 21 CFR 211.56 are included below. These sections continue to amplify the issues found within the facilities.

21 CFR 211.56(b) states that “there shall be written procedures assigning responsibility for sanitation and describing in sufficient detail the cleaning schedules, methods, equipment, and materials to be used…

21 CFR 211.56(c) states there shall be written procedures for use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents. Such written procedures shall be designed to prevent the contamination of equipment, components, drug product, containers, closures, packaging, labeling materials or drug products and shall be followed….”

During the inspection, investigators noted significant mold growth in the washroom located at the entry to the sterile manufacturing area. The ceiling of this room had been allowed to deteriorate to such an extent that it caved in. This room shares a common mezzanine with the adjacent sterile processing rooms.

Your response does not identify any efforts to identify the mold growth or relate it to environmental monitoring data from the neighboring sterile suite, nor does it discuss the potential effect on the microbial quality of products made in your facility. Your response also does not discuss why this deterioration was permitted by your management until our inspection of the facility. In response to this letter, describe your investigation into the extent of mold within your facility, including within your HVAC system. Describe any additional findings of mold, corrective measures, and your investigation into the effect of any findings on product quality.

COMMENT

It appears that the facilities’ management chose not to perform any remediation of the area containing mold until the FDA arrived. When mold becomes visible to the naked eye, and no one automatically performs remediation, this suggests significant neglection of responsibilities. Also, the FDA Guidance for Industry (2004) Sterile Drug Products, requires any microorganisms isolated from such areas to be identified.

We note that a recent MHRA report of a December 2013 audit conducted at your facility discussed the findings of fungus growth within a large volume parenteral product manufactured at your facility. Please provide a full accounting of this incident and a copy of your investigation into the matter, along with corrective and preventive actions taken.

COMMENT

Because the various regulatory agencies interact with one another and share information, it is not surprising that this event became available to others. Finding fungal growth within LVP (large volume parenterals) within the ISO 5 environment begs the question as to the root source of the fungal masses. Fungal masses within LVP often are obvious to the naked eye.

The investigators noted numerous dead insects in the “Sample Pass Through” Room, located approximately (b)(4) from the Sterile Filling Line #(b)(4) of the small volume parenterals facility. In addition, dead and decaying frogs were found next to the product exit dock. Your response states that these pest infestation issues would be corrected. It also includes a commitment to remove the manufacturing waste near the entrance to the facility and to fill in the swamp-like perimeter that appeared to be serving as a harborage for vermin. Your response does not address why the observed conditions were permitted to exist in and around the manufacturing facility. In response to this letter, discuss this issue and provide details of your pest prevention program.

COMMENT

The presence of “numerous dead insects in the “Sample Pass Through” Room, located approximately (b)(4) from the Sterile Filling Line #(b)(4) of the small volume parenterals facility” again questions why management was not aware of this condition. Similarly, the presence of “dead and decaying frogs” gives pause as to why this firm was not immediately placed on “Import Alert”.

After the Warning Letter for Zhejiang Jiuzhou Pharmaceutical Co. was published in a recent Blog (8/20/14), several of my colleagues sent me comments regarding this Chinese Active Pharmaceutical Ingredient (API) source. They were particularly intrigued by the Blog because one had observed an Import Alert that was issued by the FDA on March 18, 2014, but could find no information to support it. Another individual indicated that the FDA may issue an Import Alert if there appears to exist through an inspection so many critical findings that immediate action is required.

A somewhat similar Blog in 2011 was written wherein H&P Industries had two rather significant FDA Form 483s in 2011, never was issued a Warning Letter, but rather had product seized several months later and then several months after that was issued a Consent Decree. When the FDA deems that significant harm may occur to the general population, they may take rapid action.

Another colleague purchases upstream compounds to use as starting materials. The question raised by this individual was “If API manufacturer(s) purchase materials from this company, could it cause problem?”

For an answer to this question, I refer to ICH Q7. Within ICH Q7,

7.1 General Controls

7.10 There should be written procedures describing the receipt, identification, quarantine, storage, handling, sampling, testing and approval or rejection of materials

7.11 Manufacturers of intermediates and/or APIs should have a system for evaluating the suppliers of critical materials

7.13 If the supplier of a critical material is not the manufacturer of that material, the name and address of that manufacturer should be known by the intermediate and/or API manufacturer

Zhejiang Jiuzhou Pharmaceutical Co., Ltd. (China) was inspected from October 21-24, 2013 at their active pharmaceutical ingredient manufacturing facility. Deviations from CGMP were noted in the manufacture of the API.

“Failure to implement an effective system of managing quality and failure to transfer all quality or regulatory information received from the API manufacturer to your customers.

Your trading company, hereafter referred to as Zonebanner, purchased APIs from an outside supplier and relabeled them without the oversight of a quality unit. The information from the original certificate of analysis, generated by the actual manufacturer, was transferred to a new certificate of analysis on Zhejiang Jiuzhou Pharmaceutical Co. letterhead with no information about the original manufacturer or analytical laboratory performing the analyses. In addition, a new label identifying Zhejiang Jiuzhou Pharmaceutical Co. as the manufacturer was added to drums. In doing so, your firm essentially obscured the supply chain of these APIs.

Zonebanner had no quality system in place for the relabeling operations. In addition, we note that in at least one instance of a lot of gabapentin shipped to the U.S., the retest date from the original manufacturer’s certificate of analysis (November 2013) was changed to an expiration date listed as eleven months later (October 2014) on the new certificate of analysis…

In response to this letter, provide details of the proposed quality system to be implemented at Zonebanner. Describe procedures and provide examples that demonstrate that traceability is maintained for currently distributed APIs and that information sent to customers includes an accurate representation of the manufacturer and analytical testing laboratory. In addition, provide your rationale for the expiry extension of the gabapentin lot described above. If this or other similar extensions were unsupported, then describe your intended actions for the lot(s) in question.”

COMMENT

Unfortunately, this is not the first of these kinds of issues arising within China. Transferring of information to a new certificate of analysis on Zhejiang Jiuzhou Pharmaceutical Co. letterhead with no information about the original manufacturer or analytical laboratory performing the analyses obscures the supply chain of APIs. In addition, changing the original manufacturer’s certificate of analysis to an expiration date listed as eleven months later on a new certificate of analysis.

MISBRANDING VIOLATIONS

“In addition to violating CGMP, your firm shipped a misbranded active pharmaceutical ingredient to the U.S. As described above, according to our inspection, your firm prepared a certificate of analysis (COA) for gabapentin on your firm’s letterhead, indicating that the product was manufactured by your firm, Zhejiang Jiuzhou Pharmaceutical Co., Ltd, when in fact it was not. The gabapentin was manufactured by (b)(4). In addition, the expiration date on your firm’s COA is not one supported by the COA from the original manufacturer, (b)(4).

Moreover, your firm relabeled gabapentin and included on the label an official stamp that identifies your firm, Zhejiang Jiuzhou Pharmaceutical Co., Ltd, as the manufacturer of the product, rather than the actual manufacturer, (b)(4). Based on our findings, the active pharmaceutical ingredient, gabapentin, is misbranded within the meaning of Section 502(a) of the Act [21 U.S.C. 352(a)] in that its labeling is false or misleading in any particular. See also 21 CFR 201.1(h)(2).”

COMMENT

Including on the label an official stamp that identifies this firm as the manufacturer of the product, rather than the actual manufacturer constitutes misbranding within the meaning of the labeling as false or misleading.